Editors' ChoiceCardiovascular Disease

A New Hope for chronic myocardial ischemia

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Science Translational Medicine  11 Jul 2018:
Vol. 10, Issue 449, eaau1975
DOI: 10.1126/scitranslmed.aau1975

Abstract

Intramyocardial injection of mesenchymal stem cell–derived extracellular vesicles enhances angiogenesis and improves cardiac function in a swine model of chronic myocardial ischemia.

In the climactic scene of the classic film Star Wars Episode IV: A New Hope, Luke Skywalker must maneuver his X-wing starfighter down a narrow trench before firing two torpedoes into a miniscule shaft opening of a thermal exhaust port to destroy the evil Galactic Empire’s instrument of planetary destruction, the Death Star. Only precise delivery at the specific location would achieve the desired effect. Using the same principle, Potz et al. examined the potential of direct injection of mesenchymal stem cell (MSC)–derived extracellular vesicles (EVs) into the region of the heart most vulnerable to ischemic injury to attempt to treat chronic myocardial ischemia, a serious complication of cardiovascular disease that can lead to heart attack and/or heart failure.

Many chronic myocardial ischemia patients are not good candidates for surgical interventions, and there are no approved medical therapies that effectively restore blood flow to the heart. MSC EVs are known to induce angiogenesis in a variety of preclinical models; however, there have been few large animal model demonstrations of MSC EV efficacy. Potz et al. utilized a Yorkshire swine model to assess the impact of intramyocardially injected MSC EVs compared with a saline injection control group. They found that animals receiving a single MSC EV injection exhibited increased blood flow, stroke volume, and cardiac output compared with controls. Examining the region of injection, the authors found increased capillary and arteriolar density in the EV-injected animals, suggesting a causal relationship between angiogenic activity of MSC EVs and the functional cardiac effects observed. Further, the authors observed in a pilot study that intravenous delivery of MSC EVs through auricular veins had no effect, highlighting the importance of precise local delivery. Last, the research team reported that the mitogen-activated protein kinase (MAPK) and AKT/eNOS signaling pathways were activated in EV-injected animals, suggesting a mechanism of EV action that could be critical for eventual clinical translation.

Although this report bolsters the potential of MSC EVs for cardiac therapy, barriers to translation remain. For example, intramyocardial injection is highly invasive. Furthermore, these studies were performed in young, otherwise healthy animals, and thus comorbidities typically associated with chronic myocardial ischemia were not recapitulated in this model. However, the reported results provide a foundation for future MSC EV studies in the heart in additional large animal models, as well as in clinical trials.

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